Coating for small bodies

ABSTRACT

Coated bodies and a process, apparatus and article of manufacture for coating bodies in a non-fluidized state, including tablets, by producing an upward spray of coating fluid by means of a two-fluid nozzle as defined herein and contacting said bodies with said spray of coating fluid in a non-fludized state; wherein, before contacting the bodies with said spray, providing the bodies with a spinning movement by acentral impact of gas jets directed upward to intersect the centerline of said spray; guiding the spinning bodies by said gas jets towards a central position over the two-fluid nozzle, thereby increasing the number of suspended bodies contacting the spray; providing atomization gas to the two-fluid nozzle in an amount less than the one which after moderation by means of muffling gas would scatter the bodies in the spray zone; and pneumatically muffling the atomization gas just above the nozzle to reduce the spray body scattering effect thereof.

RELATED APPLICATIONS AND PATENTS

The present application is a division of application Ser. No. 10/662,816filed Sep. 16, 2003, which is a continuation-in-part of application Ser.No. 10,627,914, filed Jul. 28, 2003 now abandoned, which is acontinuation of application Ser. No. 09/709,560, filed Nov. 13, 2000 nowabandoned, which is a division of application Ser. No. 09/223,311, filedDec. 30, 1998 (now U.S. Pat. No. 6,209,479).

FIELD OF THE INVENTION

The present invention relates to coating of small bodies, includingtablets. Herein the term “tablets” is used in a broad sense, comprising,within the pharmaceutical industry, not only proper tablets but alsopills and capsules, and in the fertilizer and agro-chemical industrypellets and granules.

Thus, the invention is not limited to any specific industrial area butis applicable in connection with the coating of any type of bodieshaving mean body sizes in the range from approximately 2 mm to 50 mm,especially from 3 to 30 mm.

Coating operations are also important in several industrial areas otherthan the above-mentioned, such as in the detergent industry and in theconfectionary and food industry as well as in the manufacture ofcatalysts.

Coatings may be applied to such small bodies for several purposes, e.g.to obtain a desired color or other visual improvements, to obtain asustained or otherwise controlled release of active ingredients, toprotect the bodies against humidity and oxygen from the environment, toincrease resistance against abrasion and to prevent dust formation inthe particular case of handling tablets.

BACKGROUND OF THE INVENTION

Most tablet and small body coating is still done using the same methodas in the last 50 years, i.e. coating in the pan coaters or drum coatersin spite of the fact that these apparatuses have serious drawbacks.

These drawbacks are due to the fact that in both processes only one sideof the bodies' surfaces is exposed to a spray of coating liquid at atime. These apparatuses also have the drawback that the inlettemperature of the drying gas has to be lower than the maximallypermitted product temperature since the cooling effect from the solutionevaporation is not realized in the coating zone. This makes theevaporation capacity of the process gas low, necessitating a low sprayrate and resulting in a long process time. The spray rate must befurther reduced to prevent the bodies from sticking together on the pan,which fact also decreases the handling capacity.

Because of these drawbacks associated with the pan and drum coatersseveral processes have been suggested for coating particulate materialsor small bodies, such as granulae, pellets or crystals.

The first improvement was the use of a fluidized bed for suspending theproduct. The coating solution was applied to the product as sprayingfrom the top counter-current to the airflow. In comparison to the pancoater, the drying capacity was increased due to the drying capabilityof the fluidizing air. However, the inlet temperature of thedrying/fluidizing air was limited by the maximally acceptable producttemperature since the cooling effect of the coating solution is notrealized by the product in a countercurrent coating process.

To improve the efficiency of coating it is suggested in U.S. Pat. No.2,648,609 (Wurster) to impart a turbulent flow of the drying andsuspending air by conducting it through ducts in a rotating disc beforeintroduction below a screen over which pass the tablets being coated.The purpose of using a turbulent air flow was to obtain a tumblingaction on the tablets to make the coating thereon more even. By thisprocess the coating liquid was applied cocurrently to the air flow,enabling higher inlet temperatures of the drying air, but the treatmentwas rather severe to the tablets due to contact between the tabletsduring their tumbling movement. Besides, the tumbling created by theturbulent flow of drying air was insufficient to ensure an evendistribution of the coating spray on all surfaces of each particle.

Moreover, processes involving a proper fluidization of the articles tobe coated are less suitable for tablets of the size usual inter alia inthe pharmaceutical industry because, given their size and shape, thesecannot easily be fluidized. Therefore, the fluidized bed was modifiedinto a so-called spouting bed. In this design, the perforations in thebottom of the bed for the process air are concentrated in one or morelocations so that the process air at those points has enough velocity totransport the tablets pneumatically. The spray nozzle is placed in thebottom of the fluid bed at the same place as the perforations. Thecoating solution is then applied in the same direction as the movementof the tablets, i.e. co-currently. With the process air entering wherethe spray nozzle(s) are placed and thus having the product, spraydroplets and drying air all moving in the same direction, the heat andmass transfer are more efficient. This change in design also permittedthe inlet temperature to be higher than the maximum acceptable producttemperature because the evaporation heat cooled the product. Althoughthis design was more efficient than the previous designs, it had arather limited equipment capacity. The product layer thickness waslimited because the process air had to keep the tablets spouting. Alsothere had to be a minimal distance between the nozzles to avoidinterference. An apparatus of this design is described in U.S. Pat. No.4,749,595 (Honda et al.).

Also U.S. Pat. No. 5,145,650 (Huttlin) discloses a fluidized bedapparatus having a plurality of nozzles. Although the area ofapplicability is indicated as including tablet coating, the apparatusseems most suitable for processing and agglomerating smaller particles.Delicate and friable tablets would be damaged by such a long residencetime in the fluidized bed.

U.S. Pat. No. 3,253,944 (Wurster) discloses a process in which theparticles to be coated are subjected to a cyclic flow. Instead of therandomness of particle motion characteristic of fluidized beds, aportion of the particles flow upwards, while being sprayed, and the restof the particles flow downwards. The flow is created by introducingdrying and flowing air at different intensity through various parts ofthe bottom of the drying chamber, for instance by having holes or otherperforations distributed in a certain pattern in the bottom. However, ithas turned out that the upward flow of particles being sprayed and thedownward flow of particles being dried are not easily kept separate andmutual contact between the two particle flows substantially disturbs theprocess.

A further improvement in coating technology was therefore obtained byintroducing a tube or partition located around the perforations wherethe process air enters and where the spray nozzle is located. Examplesof such equipment are described in U.S. Pat. No. 3,241,520 (Wurster etal.). The tube acting as partition solved 2 major problems of thespouting bed: The product layer could be increased because the tubeallowed free passage of the coated product and it solved the problem ofinterference when more spray nozzles were present in the same housing.This equipment turned out to be very suitable for coating relativelysmall objects, but it was not suitable for coating tablets. This is dueto the fact that the free-fall velocity of a tablet is comparativelyhigh, and the process air velocity has to be above this free-fallvelocity to transport the tablets pneumatically. However, this highvelocity is such that it often damages the tablets, depending on thestrength of these.

Another drawback of this equipment is the formation of agglomerates whenusing sticky coating solutions. Formation of deposits of coatingmaterial on the surfaces of the tube is a common problem, and theutilization of the drying capacity of the process air is inadequate.Serious upscaling problems are also inherent in this design.

The agglomeration problem was essentially solved by a new apparatusdescribed in WO 95/20432 (Aeromatic-Fielder AG) in which the process airwas imparted a swirling motion already before reaching the bottom plateof the apparatus, and the process air was introduced just around theupward directed nozzle. Although this apparatus involved substantialimprovements and was capable of producing more uniform high-qualitycoatings than other apparatuses it was less suitable for large tabletsthan for minor objects.

This is partly due to the fact that the object to be coated has to be ina spinning movement when hit by the spray of atomized coating liquiddroplets.

In the apparatus described in the above-mentioned WO 95/20432, theparticles to be coated are imparted a suitable spin by the shear flow inthe process air. However, this method is not suitable for objects of thesize of pharmaceutical tablets.

Therefore, there exists a need for a new process and a new apparatuscapable of creating the desired fast spin of the object to be coated,particularly when this object is a relatively large tablet or othersmall body.

Furthermore, the development of new tablet pressing machines and othermanufacturing equipment has resulted in a substantial increase of theproduction capacity thereof and, consequently, there is a need for aconcomitant increase in the capacity of coating processes andapparatuses.

There is also an increasing need for processes producing very precisecoatings; i.e., wherein all bodies in a batch, or in a lot being treatedcontinuously, receive substantially the same predetermined amount ofcoating material, and the coating must form a film or layer of eventhickness on all surfaces of each body. This is particularly importantwhere a purpose of the coating is to obtain a precise sustained releaseof, e.g., an active ingredient from a body having received the coatingor when the coating in itself comprises an active ingredient. Coatingtechnology is used extensively in the pharmaceutical industry, e.g. forthe application of non-functional or functional coats (aesthetic,protective or rate controlling polymer films) and for the deposition ofActive Pharmaceutical Ingredients (APIs) onto nonpareils(multi-particulate dosage forms). In addition to efficient techniquesfor API layering of multiparticulate systems, an accurate method ofcoating objects 3 to 30 mm in length with APIs is also desired in thepharmaceutical industry as this is the size range of most single-unitsolid dosage forms. These include tablets for oral administration andforms for other methods of delivery including human implantation.Existing methods have limitations, e.g. in terms of coating speed andaccuracy/uniformity, particularly for the deposition of low dose APIonto single-unit tablet dosage forms which requires a greater degree ofaccuracy than can be achieved using current tablet coating techniques[Walter, K. T. Coating of Objects from 3 to 20 mm in a Gas Stream,4^(th) European Coating Symposium 2001 Proceedings, 255-260 (2001)].

It has turned out that the presence of partitions, such as the tubesused in the embodiments of the above-mentioned U.S. Pat. No. 3,241,520and WO 95/20432, for tablet coating not only involves problems due tothe abrasion of the tablets thereon and the formation of stickydeposits, but also because the construction, using partitions outsidewhich a thick layer of objects to be coated is resting, demands a longresidence time for the product resulting in a low production capacityand a long lasting mechanical stress on the tablet.

SUMMARY OF THE INVENTION

The present invention relates to a novel method of coating small objectsthat enables the uniform coating of objects of sizes between 2 and 50mm, particularly between 3 and 30 mm with a high degree of accuracy.Employing the method of the invention, Relative Standard Deviations(RSD's) below 2% can be obtained for total coating contents as low as200 micrograms per object.

The present invention is based on the recognition that it is possible toavoid the above explained drawbacks of the prior art technology andfulfill the specified needs in tablet and small body coating by usingspecial pneumatic means for guiding and controlling the movement of thetablets and/or bodies to be coated and thereby omitting the partitionsused in the prior art, and by controlling and guiding the spray ofcoating liquid by means not hitherto applied in the art.

These special pneumatic means comprise a gas flow introduced with thepurpose of influencing the flow path of the atomizing air after thelatter has exerted its atomizing action, to decrease the upward liftingeffect thereof. The influencing is herein and in the attached claimstermed “muffling”.

Thus, the invention deals with a non-fluidized bed apparatus for coatingtablets and other small bodies, having within a housing at least onecoating station comprising a perforated base plate, an upward directedtwo-fluid nozzle centrally in the base plate, means for providingcoating liquid to the nozzle, means for providing atomizing gas to thenozzle and means for providing an upward gas stream through theperforations through the base plate.

The apparatus is characterized in that the upper surface of the baseplate is inclined towards the nozzle; the perforations through the baseplate are ducts arranged around the nozzle, and the upward imaginaryprolongations of the ducts intersect an imaginary center line of thespray to be produced by the nozzle; the apparatus further having meansfor pneumatically muffling the atomizing gas shortly after the latterhas left the nozzle to decrease the upward scattering effect of the gason the bodies being coated; and the area above the base plate influencedby the spray and the gas flow from the nozzle, from the muffling meansand from the perforations is without partition for the bodies to becoated.

The means for pneumatically muffling the atomizing gas currentlyregarded as most suitable for the purpose and with which most practicalexperience has been obtained, comprises outlets for gas supply meansencircling the two-fluid nozzle, and providing a rotating upward gasflow which meets the upward spreading atomizing gas stream from thetwo-fluid nozzle and deflects and modifies the stream turning it into abroader swirling flow having reduced upward scattering effect on thebodies being coated.

Very satisfactory results have been obtained when the outlets for gassupply means debouch in an annular cavity encircling the nozzle. By thisembodiment the upward swirling flow of muffle gas is forced to mergewith the atomizing gas.

However, muffling of the atomizing gas may also be achieved by othermeans. Although three-fluid nozzles have hitherto been constructed witha view of obtaining a desired gas atmosphere in the atomization zone, itmight be possible to modify a three-fluid nozzle in such a way that thegas flow in the outer zone at the nozzle tip obtains a directionpartially tangential to the atomizing gas. Thus, the invention alsocomprises embodiments wherein the means for pneumatically muffling theatomizing gas comprises a mantel surrounding the two-fluid nozzle. Thatmeans that in fact a three-fluid nozzle is used. Therefore, the term“two-fluid nozzle” is used herein and in the attached claims as coveringnot only a two-fluid nozzle proper, but also the central portions of athree-fluid nozzle, viz. the portions delivering the spray liquid andthe atomizing gas.

In contrast thereto it is an advantage of the embodiment described abovethat the muffling and the process air introduced through the ducts aresupplied from the same plenum and need no adjustment during theoperation.

Further preferred embodiments of the apparatus according to theinvention are explained in connection with the description of thedrawings below.

The invention also comprises a process for coating tablets and othersmall bodies by subjecting the tablets to an upward spray of coatingliquid produced by a two-fluid nozzle, using an apparatus as describedabove, such that said tablets or small bodies are not in a fluidizedstate, which process is characterized in that the tablets or bodies,before meeting the spray, are caused to spin by the acentral impact ofgas jets directed upward to intersect an imaginary center line of thespray, and simultaneously and subsequently, the spinning bodies areguided by the gas jets towards a central position over the two-fluidnozzle to increase the number of suspended bodies contacting the spray(up to 1000 bodies per nozzle); the two-fluid nozzle is provided withatomization gas which is adjusted to an amount less than the one which,after moderation by means of muffling gas, would scatter the bodies inthe drying zone away from the spray of coating liquid droplets; and theupward bodies scattering effect of the atomizing gas is reduced by thepneumatical muffling thereof just above the nozzle.

Preferred embodiments of the process are defined in the claims and arefurther illustrated in connection with the description of the drawingsbelow.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings:

FIG. 1 is a vertical sectional-view of an embodiment of a coatingapparatus according to the invention;

FIG. 2 is an enlarged vertical sectional-view of the central portion ofan embodiment of the apparatus according to the invention similar to theembodiment shown in FIG. 1, also showing the flow of tablets beingcoated;

FIG. 3 is a vertical partial sectional-view of a base plate as used inthe embodiments of the invention shown in FIGS. 1 and 2;

FIG. 4 schematically shows the base plate of FIG. 3 seen from below; and

FIG. 5 is a schematically vertical sectional-view of an embodiment ofthe apparatus according to the invention having more than one treatingstation.

FIG. 6 is a graphic depiction of the results of a test of the method ofthe invention.

DETAILED DESCRIPTION OF THE DRAWINGS

In the coating apparatus depicted in FIG. 1 a funnel-like member 1circumvents a coating zone 2. As depicted, the inner walls of the lowerpart of the member 1 are, in this preferred embodiment, only slightlyconical or even vertical.

Under the zone 2 a base plate 3 is shown.

As it appears most clearly from the FIGS. 3 and 4, the base plate has ahole 4 for accommodating a two-fluid nozzle as indicated by 5 in FIGS. 1and 2.

It is an important feature of the invention that at least thesubstantial part of that portion 6 of the upper surface of the baseplate 3, which is encircled by the member 1, is inclined downwardsagainst the tip of the nozzle 5 in the hole 4. The inclination of thesurface 6 to the horizontal level is preferably 5-20°, more preferably10-15°. The portion of the plate immediately adjacent to the upper partof the hole 4 may, together with the tip of the nozzle, protrudesomewhat upwards (not shown) to avoid depositing of dust in that area.

Another important feature of the invention is the provision of ducts 7through the base plate 3.

In the preferred embodiments depicted in the figures, those ducts areperpendicular to the inclined surfaces 6. However, their direction maydepart somewhat from the one perpendicular to the surface 6; they mayfor instance be less vertical than shown in the figures, in which case,the inclination of the surface 6 may be somewhat smaller than if theducts were perpendicular thereto.

Moreover, the ducts 7 are further arranged so that the upward imaginaryprolongations intersect an imaginary centerline vertically over the hole4. Which vertical line is also the imaginary centerline of the spray tobe produced by the nozzle 5.

The diameter of the ducts will typically be 1 to 1½ mm and their lengthnot less than three times the diameter.

The ducts may have different diameters to produce jets of differentintensity. Thus, the ducts near the nozzle 5 will typically be narrowerthan those more distant from the nozzle.

The distance between the ducts 7 is selected depending on the size ofthe tablets (or other types of bodies) to be coated to be from 0.2 to1.5 times the largest dimension of the tablets (or bodies).

The total area of the ducts 7 plus the area of the outlets 14, describedbelow, typically amount to 3-6% of the horizontal area of the inclinedsurface 6, preferably approximately 4%.

At the lower surface of the base plate 3 the ducts 7 have funnel-liketerminations 8 to obtain a desired flow pattern through the ducts 7.

Below the base plate 3 is a plenum 9 for providing drying air throughthe ducts 7 and muffling air for controlling the flow of atomizing airfrom the two-fluid nozzle, as explained in more detail below.

Air is conducted to the plenum through a pipe 10.

The plenum may comprise more than one compartment (not shown), therebyenabling supply of air at various pressures to various groups of ducts 7and/or means for introducing muffling gas (such as the grooves 13described below).

The two-fluid nozzle 5 receives coating liquid through conduit 11 andatomizing air through pipe 12 (FIG. 1).

As best seen in FIGS. 2, 3 and 4, the upward tapering conical walls ofthe hole 4 for accommodating the tip of the two-fluid nozzle 5 isprovided with grooves 13 which, when the nozzle is in place, forms ductsleading from the plenum 9 to outlets 14 (FIG. 2) encircling the tip ofthe nozzle. The depicted embodiment of the apparatus has six suchgrooves (FIG. 4). The grooves debouch tangentially in relation to thenozzle, for which reason air conducted from the plenum through thegrooves to the outlets 14 leaves as an upward swirling flow encirclingthe nozzle.

The operation of the apparatus is further described with reference toFIG. 2, which also shows the non-fluidized tablet/body flow during thecoating process. To fully understand and appreciate the non-fluidizednature of the progress of the tablets/small bodies while practicing themethod of the invention, however, a full and complete understanding ofthe concepts of “pneumatic transport” and “two-phase flow” systems is inorder.

Two-phase flows comprise a large segment in the field of fluidmechanics. Two-phase flows are all flows containing two or moresubstances at different phases such as gas-liquid, gas-solid orsolid-liquid. Examples include suspensions (very small particlesfloating in liquid), boiling water (or other liquid at the phasetransition temperature), atmospheric rains (condensations due tosaturation as in water here on earth, hydrogen rain on Jupiter, methanerain on Titan, etc.), rainwater seeping down through the earth,extraction of oil from soil, and fluidization. Since the field of“two-phase flows” covers a multitude of different systems, eachcombination employs its own terminology. Thus, the flow of a gas such asair through a plurality of solid bodies is correctly termed a “two-phaseflow”. Following is a description of what occurs in the different phaseswhen the process gas and the solid bodies interact.

When the amount of fluid passing through the solid bodies layer is solow that the fluid flows through the voids between each single particlewithout relocating the particles, the two-phase flow is normally termeda “creeping flow”. When the amount of fluid passing through the solidlayer is large enough to eliminate the static friction between theparticles it is termed “aeration”. The effect of “aeration” is that theproduct layer behaves like a fluid under external forces.

When the amount of gas passing through the product layer is large enoughto cause motion between some of the particles, the interaction betweenthe gas and the product layer is appropriately termed, “fluidization”.Depending on the particle sizes of the bodies and the particledistribution, the product layer will be fluidized over a range of theprocess volume flow rate. If the volume flow rate is increased, it isobserved that the product layer becomes thicker because the process gaswill create voids in the product layer when the gas passes through it.When the fluid bed is fluidized, the product layer looks like a liquidin the boiling stage.

When the amount of fluid passing through the solids layer is increasedfurther, the velocity of the gas leaving the product layer is largeenough such that the smaller sized particles are “blown off”. This stagein interaction between the gas and the solid is often called“elutriation”. During “elutriation” some particles will erupt violentlyout of the product layer. The product layer still resembles a fluid inthe boiling stage, but with larger bubbles.

When the process gas volume flow rate is increased to a level higherthan the free fall velocity of all sizes of particles in the productlayer, the particles will leave the product layer. This stage ofinteraction between the gas and the solids is usually called “pneumatictransport”. The product layer is no longer in a stable condition, and itis only a matter of time before all particles, large and small, areremoved from the product layer. All the particles will not betransported away from the product layer instantly since the process gascan only carry a certain amount of particles per volume unit of gas.Some of the particles will fall back into the product layer andparticles which come close to the equipment wall will also fall back dueto the lower velocity of the gas near the wall.

The foregoing describes the different stages in interactions between gasand solids. It would be inaccurate to categorize all such interactionsas “fluidization” and all systems that enable two-phase interactions as“fluidized beds”. Fluidization is merely one of the myriad stages oftwo-phase systems, depending on the parameters of the contact of the gasflow with the solid bodies. It will be understood and recognized bythose skilled in the art that an essential characteristic of “fluidizedbeds” is that the solids layer has a definable surface. Indeed, manyprocesses are inaccurately described in the prior art as “fluidized bed”processes. Thus, the term has been incorrectly used to describe systemssuch as those produced in a “Wurster” type apparatus or a fast movinggas stream containing or conveying entrained solids. These are not,however, true or conventional fluidized beds. In a conventional or truefluidized bed the solid particles are kept in a randomly movingfluidized condition by a stream of pressurized gas, which is forced,e.g., through perforations of a support plate, causing the solidparticles to move in a random bubbling fashion similar to a gentlyboiling liquid, but which has a definable surface. These conditionspermit the solids to flow and act like liquids and maintain a level likeliquids. See “VDI-Wärmeatlas”. 3. Auflage 1977 page “Lf1” Druckverlustin Wirbelschichten, Bearbeiter des Abschnitts Lf: Prof. Dr.-Ing O.Molerus, Erlangen; Geankoplis, “Transport Processes and UnitOperations”, 3d Ed., NJ, pp. 123-127 & 352-253, (1993) and U.S. Pats.Nos. 5,399,186 and 4,495,163. It is important to emphasize thisdistinction since true or conventional fluidization causes the solids toflow and act like liquids.

The prior art is of course replete with illustrative demonstrations ofthe distinctions between “fluidized bed” and “non-fluidized bed” systemsand methods. For example, attention is directed to the disclosure inU.S. Pat. No. 4,338,187 which relates to a method for the delivery ofparticulate solids to a reaction chamber and to internally mixing theparticulate solids with a fluid, principally feed, at the reactor. It isdesirable to regulate the flow in this system to below +/−5%, preferablybelow +/−2%. To achieve this close control on solids flow rate, thedampening characteristics of a non-fluidized bed are employedsimultaneously with the flow relationships, which are inherent withfluidized bed control systems. The essential feature of the controlsystem is the localized fluidization of the solids just above theconduit inlet. In no instance is the amount of fluidization gassufficient to fluidize the entire bed of solids in the reservoir.Rather, the amount of gas added is sufficient to only locally fluidizethose solids in the region of the conduit inlet. The patent demonstratesthe inherently different dynamics associated with “fluidized” and“non-fluidized” systems, respectively.

U.S. Pat. No. 4,412,909 relates to methods and apparatuses for theextraction of oil from a moving bed of carbonaceous material such as oilshale wherein a “non-fluidized” bed of the carbonaceous material isexposed to a plurality of rotatable apertured cylindrical rollers andpassing through the moving bed at spaced points a plurality of discretestreams of nonoxidizing gas heated to different temperaturessufficiently high to educe different weight fractions of oil from theshale as vapors into the gas streams; and separating the differentweight oil fractions from the gas streams. The patent emphasizes theimportance of maintaining “non-fluidized” conditions in the system.

U.S. Pat. No. 4,456,504 relates to a method and apparatus for processinggranular solids. The patent discloses an improved method for carryingout the thermal processing of the granular solid in a staged turbulentbed which includes the steps of passing the granular solids downward asa continuous moving body of solids through a reactor vessel and passinga gas upward through the reactor vessel in a generally countercurrentflow to the downward movement of the body of solids at a velocitysufficient to fluidize a first fraction of granules but insufficient tofluidize a second fraction. The crux of the invention resides in therecognition of the different physical mechanisms inherent innon-fluidized systems as opposed to fluidized systems and takingadvantage thereof to achieve a particularly desired result not otherwiseachievable.

U.S. Pat. No. 4,479,308 relates to a method and system for recoveringheat from a hot particulate solid. The particulate solid is treated in asystem countercurrently with a gaseous fluid that achieves“fluidization” of only a portion of the particulate solid and leaves asubstantial portion thereof non-fluidized. The patent is another exampleof recognition by the prior art of the critical distinctions that existbetween a “fluidized” and a “non-fluidized” system.

U.S. Pat. No. 6,270,801 relates to the processing of a particulate solidin a processing chamber wherein an upwardly flowing gas stream contactsthe mass of particulate solid. The patent emphasizes the importance ofmaintaining “non-fluidization” of the particulate solid. The criticaldistinctions existing between “fluidized” systems on the one hand and“non-fluidized” systems on the other hand when treating particulatesolids are discussed in detail in the disclosure of the patent.

U.S. Pat. No. 5,718,764 discloses a method and apparatus for coatingdiscrete solid particles and discusses the differences that result whenconducting such coating operations where the particles are in a“fluidized” state as opposed to a “non-fluidized” state.

In the method of the invention the bodies undergoing coating are not ina true “fluidized” state, i.e., the mass of bodies in the coatingchamber do not constitute a true “fluidized bed”. Thus, the bodies haveno definable product layer and they flow in a ballistic path with norecognizable or defined surface to the mass of bodies in the coatingchamber.

A significant advantage of the method of the invention resides in thefact that it enables the coating of an even layer on the bodies, i.e.,the deposition of a layer of even thickness on each individual bodycoated. A further advantage is that the method of the invention enablesthe even distribution of the coating material over the entirety of thebodies undergoing coating. The ability to create a coating layer of eventhickness on bodies is important, particularly where the coat operatesas a functional coat, for example, on tablets for sustained releasepurposes, or as an enteric coat. In addition, the ability of the methodof the invention to distribute the coating, e.g., an active ingredientevenly on objects in the 3 to 30 mm range (e.g., under a layer ofprotective coating) is also very important.

Thus, following the method of the invention, one can distribute theactive ingredient on the intended substrates at RSD values as low as 5%or less; in some cases as low as 3% or less.

With regard to the “even distribution” of the coating on the substrates,it is easily demonstrated (e.g., by using a technique that measuresvariations in the color of the applied coat) that one can obtain fullcoverage of the intended substrates with less coating material utilizingthe method of the invention as opposed to traditional coatingtechniques.

Although it may be intuitive that a method that creates a coating layerof even thickness necessarily includes the even distribution of thecoating material on the bodies undergoing the coating operation, such isnot the case. Experience has taught that it is much more difficult toevenly distribute a coat of, e.g., an active ingredient, on bodies thana normal esthetic coat. Normally, when tablets are analyzed aftercoating with an esthetic coat and an active ingredient coat, largervariations in evenness of distribution are detected with the activecoat. It is more difficult to make an even distribution of active drugcoat layer than an esthetic coat because of the relative amounts appliedand the generally poor film-forming characteristics of active coats.

It is common, of course, to deliver drugs orally. This means that thedrug or active must be incorporated in a tablet, pill or capsule, whichmust be large enough to be picked up from a surface by a human hand, butnot so large that it is difficult to swallow.

The first requirement for tablet pressing is that the material be freeflowing, which means that the material must be granular. This freeflowing capability is essential for achieving the same tablet strengthand tablet weight throughout the batch. The transformation of the baseformulation into granules is normally carried out in a so-called “wetprocess”. The active drug is either crystalline or amorphous, and bothtypes are problematic when a wet process is used for tabletting. Thecrystalline drug in a wet process is either in a solid phase ordissolved by the process liquid. When the crystal changes between thesolid and the dissolved phase, and back again to the solid phase, thecrystal can change form, with the consequence that it may lose activityor create side effects. Sometimes it is necessary to use solvents thatare unable to dissolve the crystals. The amorphous drug can be eitherhydrophilic or hydrophobic, each category creating problems in thegranulation process and in the distribution of the active in thepressing material. The requirement for the active distribution fromtablet to tablet is normally set by the FDA at ±5%.

When a drug is highly potent, which means only a very small amount ofmaterial must be distributed as evenly as possible (the amount of activein the tablets can be as low as 0.05%) significant challenges arepresented. Often the accuracy of the distribution can first bedetermined when the tablets are produced. If the goals are not met, andthe active is precious and recoverable, the batch may simply sent forrecycling. Manufacturers must go to great lengths to ensure the evendistribution of the active to satisfy the FDA demand that thedistribution be inside the above-mentioned tolerance.

The problem of even distribution is exacerbated in the case of aparticularly potent drug which is difficult to incorporate in theformulation and challenging to recover. According to one method of theprior art, inert tablets were prepared and, after passing the hardness,disintegration and tablet strength tests, small holes were drilled inthe tablets and the active drug was placed in the holes and the tabletssealed. The last step in the process is the coating of the tablets. Thesize and expense of the equipment required for this elaborate procedureis considerable and the handling of tablets laboriously slow. The dailymaintenance and adjustment of this equipment is considerable, timeconsuming and expensive.

The method of the invention is particularly advantageous in solving thisproblem. Thus, the method of the invention enables the incorporation ofvery small amounts of active drug on tablets and other small bodieswhile ensuring an even distribution of the material from body to body.

According to the method of the invention the tablets or small bodies tobe coated obtain a spinning movement of high-velocity before reachingthe spray of coating liquid and, at the same time, the scattering of theflow of tablets by the atomizing air from the two-fluid nozzle isavoided, for which reason a high concentration of tablets can bemaintained in the spraying zone.

This is apparent from a study of FIG. 2 which shows that tablets arefalling downwards in the periphery towards the base plate 3. Beforetouching the plate they obtain a radially inward movement due to theinfluence of an air flow sucked into the flow above the nozzle and alsoby the influence of gas jets provided from the plenum 9 through theducts 7. However, the main effect of these gas jets is to create a fastspinning movement of the tablets before they reach the spray from thenozzle 5. The gas jets blown in through the ducts have a velocity of80-180 m/sec., preferably 100-150 m/sec.

If no special measures were taken to reduce the scattering effect of theatomizing air from the two-fluid nozzle, the tablets would be blown upat a considerable height and, therefore, the tablets would be spread,which means that only a minor portion of the spray-coating liquid wouldbe deposited on the surfaces of the bodies. Besides, such vigorous flowmay damage the particles and increase the abrasion thereof.

The process of the present invention embodies two measures to avoid thisdisadvantage. Firstly, the amount of atomizing air is reduced comparedto the amount normally used for nozzles of the type in question. Thismeans that the droplet size of the spray becomes larger than usual fortwo-fluid nozzles, but due to the sizes of the tablets this is of noimportance as to the quality of the final coating.

Secondly, the momentum of atomizing gas is stifled by muffling gasintroduced through the grooves 13 to the outlets 14. In the depictedembodiment, the muffling gas leaves the outlets 14 at substantially thesame velocity as the one of the jets from the ducts 7 fed from the sameplenum 9. However, when the plenum has more compartments it may bepossible to adjust the amount of muffling gas and the amount of gasintroduced through the ducts 7 independently. The muffling gas creates aswirling flow that rapidly influences the flow of atomizing air from thenozzle. Therefore, the last-mentioned flow also becomes swirling and,consequently, the upward velocity component and thus the tablet liftingcapability becomes lower, whereas the size of the spray cloud becomessomewhat broader

This means that the spinning particles passing along the incliningsurface of the base plate 3 when reaching the spray only receive amoderately lifting influence and their residence time in the zone wherethey are hit by the spray droplets is relatively extended.

Instead of a muffled two- or three-fluid nozzle another low momentumspray device, e.g. electrostatic or ultrasonic spray means, also beinglow momentum spray devices, can be considered for use in the apparatusand the process of the invention.

The apparatus and the process according to the invention may be usedboth for batch-wise and continuous tablet coating.

Apparatuses of both types may comprise one or several coating stations.When more than one coating station is applied, they may be operatedeither independently as a parallel system or they may be connected inseries.

As depicted in FIG. 5 the coating stations may be separated by a wall 15over which the tablets pass at random when lifted by the coating sprayflow.

Passage of tablets from one coating station to another may also beobtained by a controlled permanent or adjustable tilting of theapparatus.

For continuous operation an apparatus according to the invention maytypically comprise five coating stations connected in series. Passagefrom one station to the next is controlled by tilting the battery ofstations or by affecting the product container shape such that thetablets can move forward but not backwards through the apparatus. Thecoating capacity of such a multi-station apparatus will be approximately3,000 tablets/min. when a coating layer of 20-30 micrometers shall beobtained using an aqueous or organic coating solution. The totaltreatment time for each tablet for passing all five stations will beapproximately 10 sec.

In such a battery of coating stations coating materials of differentcomposition may be applied to obtain a multi-layer coating in only onepassage of the tablets through the battery of coating stations.

In commercial use the apparatus according to the invention will ofcourse be provided with equipment for automatic operation based onsignals obtained by continuously or periodically monitoring of variousparameters, such as flows or temperatures of gasses or tabletsintroduced or withdrawn from the apparatus or other parameters whichwill be obvious to a person skilled in the art.

The invention is further elucidated by the following example.

EXAMPLE 1

A coating operation was performed in an apparatus as the one shown inFIG. 1

The size of the apparatus was such that the horizontal diameter of theinclined surface 6 was 40 mm.

The tablets to be coated were circular and had the following dimensions:

diameter 7.0 mm height 4.5 mm surface area 6.6 .times. 10⁻⁵ m²

The weight of each tablet was 0.164 g and the number of tablets in thebatch was 200 corresponding to a total weight of 32 g.

The coating liquid was a 20 weight % aqueous solution of Opadry®YS-1-7003, which is a coating based on hydroxypropyl methyl cellulose.

Ambient condition: temperature 19° C. relative humidity 64% Inlettemperature of gas 108° C. introduced to the plenum Flow rate forprocess gas 0.00684 m³/sec. introduced to plenum 9 Velocity of processgas through 128 m/sec the ducts 7 and the outlets 14 Atomizing pressure2.5 bar Atomizing gas flow rate 0.0004 Nm³/sec. Coating solution sprayrate 8.25 g/min. Process time 40 sec. Coating thickness 42 μm

The resulting coated tablets were subjected to various examinations andtests. By these no damage of the tablets was observed and the coatingwas estimated as being of very even thickness and of high-quality.

Several other runs were made employing the apparatus of FIG. 1 to coattablets and using the process of the invention, and the results obtainedthereby indicate that the invention enables a faster coating of eachtablet than possible when using any of the commercial coatingapparatuses. The method of the invention also enables the coating oftablets that are too delicate or friable to be coated by knowncommercial processes or apparatuses.

EXAMPLE 2

A study was undertaken to determine the accuracy of the method of theinvention in applying small amounts (theoretical doses of 200 and 400micrograms per tablet) of an active pharmaceutical ingredient (API) ontoconventional tablets and to investigate the influence of the followingair suspension process parameters on the uniformity and yield of APIcontent per tablet: batch weight, API solution concentration, API dose,solution spray rate and atomizing gas pressure.

Methods of evaluating coating uniformity include mass variance of thecoated tablets and variance of the tablet API content [Tobiska, S. andKeinebudde, P. Coating Uniformity Influence of Atomizing Air Pressure,Pharm. Dev. Tech., 8(1), 39-46 (2003); Tobiska, S. and Kleinebudde, P.Coating Uniformity and Efficiency in a Bohle Lab-Coater using OvalTablets, Eur. J. Pharm. Biopharm., 56, 3-9 (2003) and Uniformity ofDosage Units <905>, United States Pharmacopeia 26/National Formulary 21,US Pharmacopeial Convention, Inc., 227-229 (2003).

However, at very low active levels mass variance cannot be used as ananalysis method [USP, supra]. For this study, the RSD of the API contentwere used to evaluate the inter-tablet coating uniformity of the coatingmethod of the invention in applying low doses of an API ontoconventional tablets.

Granules were prepared using a PRECISION GRANULATOR™ (MP 2/3,Aeromatic-Fielder Ltd.) with 88 wt. % Lactose (Pharmatose 200M, DMV), 5wt. % Polyvinylpyrrolidone (K29/32, ISP; delivered via a 15 wt. %solution), 5 wt. % Microcrystalline cellulose (Avicel PH-101, FMC) and 2wt. % Crospovidone (Polyplasdone XL10, ISP). After milling (197S, QuadroComil; 94R screen; 1500 rpm) and sieving, milled granules <1 mm sizewere blended with 1% magnesium stearate prior to tabletting in a rotarytablet press (R 190-FT, Courtoy; 7 mm flat-faced, bevelled edged punchand die sets). The uncoated placebo tablets were characterized forweight variation, hardness (PTB 300, Pharmatest) and friability(Electrolab). Tablets were coated with a base coat followed by an APIcoat (API coat 1 or API coat 2) employing the procedure described inExample 1. Coating formulations and process conditions are given intables 1 and 2.

TABLE 1 Base and API Coating Formulations Base Coat API Coat 1 API Coat2 Material (wt. %) (wt. %) (wt. %) Purified water 94.45 94.35 93.45Hydroxypropyl methylcellulose 5 5 5 (Methocel E3 PREM LV, Dow)Polyethylene glycol (Carbowax 0.05 0.05 0.05 3350, Union Carbide)Polyvinylpyrrolidone 0.5 0.5 0.5 (Plasdone C-15, ISP) Propranolol 0.00.1 1.0

TABLE 2 Tablet Coating Process Conditions Inlet Plenum Atomizing BatchAirflow Air Pressure Gas API Solution Volume Spray Batch Weight RateTemp. (cm Pressure Concentration Applied Rate ID (g) (CMH) (° C.) WC)(Bar) (wt. %) (mL) (mL/min) F 30.00 17.4 120 1000 2.3 0.1 89.80 4.0 G30.00 17.4 120 1000 3.0 0.1 89.80 6.0 A 60.00 21.3 120 1700 3.0 0.189.80 8.0 H 60.00 21.3 120 1700 2.3 0.1 89.80 6.0 E 30.00 17.4 120 10002.3 0.1 44.90 6.0 J 30.00 17.4 120 1000 3.0 0.1 44.90 6.0 K 30.00 17.4120 1000 2.3 0.1 44.90 4.0 B 30.00 17.4 120 1000 3.0 0.1 44.90 4.0 C30.00 17.4 120 1000 3.0 0.1 44.90 4.0 D 30.00 17.4 120 1000 2.3 1.0 4.494.0

At least 10 coated tablets per batch were analyzed. Methanol (HPLCgrade, EM Science) was used as the extraction solvent. The HPLC system(1100 Series, Agilent Technologies) consisted of an autosampler, aquarternary pump, a variable wavelength UV detector and a BaseDeactivated Silica C-18 column (5 μm; 150 mm×4.6 mm). The mobile phasewas composed of 70% 50 mM phosphate buffer (pH 2.6-2.9): 30%Acetonitrile. All solutions including the sample supernatant werefiltered through a 0.45 micron membrane filter (Sartorius). Thedetection wavelength, injection volume, injection run time and mobilephase flow rate were 292.4 nm, 40 μL, 10 minutes and 1 mL/min,respectively.

Uniformity of Coating Process

The best results were from Batch H, which had the lowest API content RSDof 3.0% and the second highest API yield of 78.9% (FIG. 6 and table 3).The API content RSDs were 5.0% or less for all but two batches (thecauses of these two high values are discussed below).

TABLE 3 API Content RSDs and API Yields Batch ID API Content RSD (%) APIYield (%) F 3.8 70.0 G 4.6 67.1 A 8.9 79.4 H 3.0 78.9 E 4.9 67.3 J 4.463.6 K 4.7 61.8 B 3.8 63.1 C 5.0 61.6 D 13.0 65.0

Influence of Process Variables on API Content Uniformity and Yield BatchWeight

The theoretical API dose for both batch weights of 30 g (229 tablets)and 60 g (458 tablets) was 200 micrograms per tablet. Plenum pressurewas increased from 1000 cm WC (30 g batches) to 1700 cm WC (60 gbatches) to maintain proper tablet movement during coating. From table3, the two 60 g batches had a significantly higher mean API yield(79.2%) than the 30 g batches (63.5%). With a larger batch size, thereis more surface area to collect the liquid droplets, resulting in higherAPI yields. The trend in API content RSDs is not as clear compared tothe yield. Although the 60 g batches had a higher average RSD of 6.0%(vs. 4.6% for the 30 g batches), the API content RSD of batch A is mostlikely high because the highest spray rate was used for this batch.

API Solution Concentration

Two API solution concentrations were used, 0.1% (API Coat 1) and 1.0%(API Coat 2). To maintain the 200 micrograms theoretical API dose, thetotal volume of coating solution was decreased by a factor of ten forthe batch coated with API Coat 2. Mean API contents (and API yields) ofthe various batches were found not to be significantly different fromeach other (FIG. 2). While API solution concentration did not appear tohave a significant effect on API yields, the content RSD valuesindicated that API solution concentration influenced coating uniformity(table 3). The average content RSD of the 0.1% API solution batches was4.6 while that of the 1.0% API solution batch, at 13.0%, was the highestRSD among all of the batches. With a lower API solution concentration,the API is distributed into a larger volume of coating solution.Deposition of the API onto the tablets then takes place over a longerperiod of time, resulting in a more random coating process.

API Dose

The spray times for the 400 microgram theoretical API dose batches weretwice as long as those for the 200 microgram batches in order to keepall other parameters constant. All batches had API content RSDs lessthan 5.0% (table 3). The 400 microgram batches had a mean API contentRSD of 4.2% while the 200 microgram batches had a mean API content of4.6%. The 400 microgram batches were observed to have a slightly highermean API yield.

Solution Spray Rate

Three different spray rates were used, two for each batch size. Themaximum spray rate differs for each batch size as drying rate increaseswith an increased amount of surface area. Therefore the same two sprayrates could not be used for both batch sizes. For the 60 g batches, theAPI content RSD increased significantly when spray rate was increasedfrom 6.0 to 8.0 mL/min (table 3). With a spray rate of 8.0 mL/min, batchA had an RSD of 8.9%, one of only two batches higher than 5.0%. However,large differences in RSDs were not observed for the 30 g batches at thespray conditions used. All 30 g batches with 0.1% API coat solution hadRSDs less than or equal to 5.0%. When spray rate was increased from 4.0to 6.0 mL/min, the API yields of the 30 g batches ranged between 61.6%and 67.3%.

Atomizing Gas Pressure

At the two atomizing gas pressures selected (2.3 and 3.0 bar), all ofthe API content RSDs were less than or equal to 5.0% and the API yieldsranged from 61.6% to 67.3% (table 3).

Based on the results of this study, the coating process of the inventionenables one to uniformly apply low doses of APIs to single-unit dosageforms such as pharmaceutical tablets. API content RSDs of less than 5.0%can be achieved for theoretical doses as small as 200 micrograms. TheAPI yields obtained ranged from 61.6% to 79.4%, with the 60 g batcheshaving the highest values. For the purpose of applying low doses of APIsto single-unit dosage forms, the goal is to obtain the lowest APIcontent RSD and the highest API yield. It will be apparent to thoseskilled in the art that process and formulation may be optimized tofurther improve the coating uniformity and coating yield in anyparticular specific application without departing from the principlesand spirit of the present invention.

EXAMPLE 3

The procedure of Example 2 was followed in coating a batch of 50 inertcores (8 mm) with a solution of Taxol® (0.25%). The RSD of the uncoatedcores was 1.456. The average coating weight gain was 164 microgramsyielding an RSD of less than 2%, more specifically, 1.76%. Thus,according to the method of the invention, coating RSDs substantiallyequivalent to the RSDs of the substrates to be coated are obtainable.

It will also be understood by those skilled in the art that the methodand apparatus of the invention is suitable for the coating of anyplurality of small bodies with any suitable active pharmaceuticalingredient (API).

1-18. (canceled)
 19. A plurality of bodies having been subjected to a non-fluidized bed coating process whereby each of said bodies is coated with at least one coating containing a low dose of an active pharmaceutical ingredient (API) wherein the relative standard deviation (RSD) between the said at least one coating on said bodies is equal to or less than about 5%.
 20. The plurality of bodies of claim 19 wherein said dose of API is equal to or less than about 400 micrograms.
 21. The plurality of bodies of claim 19 wherein said dose of API is equal to or less than about 200 micrograms.
 22. The plurality of bodies of claim 19 wherein said RSD is less equal to or less than about 3%.
 23. The plurality of bodies of claim 19 wherein said RSD is less equal to or less than about 2%.
 24. The plurality of bodies of claim 19 wherein the dose of API is equal to or less than 400 micrograms and wherein the RSD is equal to or less than about 3% and the at least one coating is evenly distributed over the bodies. 25-33. (canceled)
 34. The plurality of bodies of claim 19 wherein the bodies have mean sizes in the range of from approximately 2 mm to approximately 50 mm.
 35. The plurality of bodies of claim 34 wherein a perforated base plate having an inclined upper surface; the bodies have mean sizes between approximately 3 mm and 30 mm.
 36. The plurality of bodies of claim 34 wherein the at least one coating is evenly distributed over each of the bodies.
 37. A coating applied to articles in a non-fluidized bed coating process whereby each of said articles is coated with at least one coating wherein the relative standard deviation (RSD) between the said at least one coatings on said articles is equal to or less than about 5%.
 38. The coating of claim 37 wherein said RSD is less equal to or less than about 3%.
 39. The coating of claim 37 wherein said RSD is less equal to or less than about 2%.
 40. The coating of claim 37 wherein the articles have mean sizes in the range of from approximately 2 mm to approximately 50 mm.
 41. The coating of claim 37 wherein the bodies have mean sizes between approximately 3 mm and 30 mm.
 42. The coating of claim 34 wherein the at least one coating is evenly distributed over each of the articles.
 43. The plurality of bodies of claim 42 wherein the bodies have mean sizes between approximately 3 mm and 30 mm.
 44. A coating applied to articles in a non-fluidized bed coating process whereby each of said articles is coated with at least one coating evenly distributed over the surface of the articles and wherein the relative standard deviation (RSD) between the said at least one coatings on said articles is equal to or less than about 5% and articles have means sizes in the range of from approximately 2 mm to approximately 50 mm.
 45. The coating of claim 44 wherein said RSD is less equal to or less than about 3%.
 46. The coating of claim 44 wherein said RSD is less equal to or less than about 2%.
 47. The coating of claim 44 wherein the articles have mean sizes between approximately 3 mm and 30 mm.
 48. The coating of claim 44 wherein the bodies have mean sizes in the range of from approximately 2 mm to approximately 50 mm. 